The set of studies represented by Project 2 of the Program builds on the collaboration between the clinical and the basic scientists. We will characterize the vascular biological phenomena associated with brain arteriovenous malformations (BAVMs). The Strength of this project is the parallel mechanistic investigations coupled with a large new case enrollment, thus allowing correlation of clinical data with biological tissue assay data. This linkage is unique and important because BAVMs represent a broad spectrum of physiological alterations. Three primary types of tissue will be studied: (1) BAVM nidus (n=80), a tangle of abnormally dilated vessels forming a direct high flow arteriovenous shunt without an intervening capillary bed; (2) adjacent structurally-normal brain (n=40); and (3) control brain from epilepsy surgery (n=40). Both human surgical specimens and cell culture systems will be utilized. Our hypotheses are the following: (1) BAVMs represent a relative increase in (a) endothelial cell (EC) mitogens, vascular endothelial growth factor (VEGF), compared to (b) the Tie-2 / angiopoietin (Ang) pathway that recruits and maintains periendothelial support structures (e.g., smooth muscle cells and pericytes). This imbalance initially leads to micro-shunt formation (increased flow). BAVM growth is favored by increased Ang-2 signaling when VEGF receptor (VEGF-R) activation is ongoing. BAVM growth and regression will require modulation of extracellular matrix. (2) Matrix metalloproteinases (MMPs) degrade the extracellular matrix in the BAVM vessels. Excessive degradation of the extracellular matrix will predispose the BAVM vessel to rupture (= intracranial hemorrhage). (3) Mechanistically, supra-physiological levels of Ang-2, unopposed by Ang-1, down-regulates Tie-2 expression in BAVMs as part of a feedback mechanism or by blocking Ang-1 stimulation on Tie-2. Significance: Elucidating the pathways involved in abnormal angiogenesis in BAVMs can facilitate identification of clinically relevant biological phenomena whose mechanisms can be further studied in cell culture and animal models. Correlation of biological data with clinical data may aid in prediction of clinical behavior of BAVMs and risk-stratification for clinical management.